Stable liquid compositions of posaconazole

ABSTRACT

The present invention relates to stable, room-temperature storable, liquid compositions comprising posaconazole. The liquid compositions, when stored at room temperature conditions, exhibit no significant coloration and no significant loss in chemical stability. The liquid compositions also exhibit good dilution stability with no evidence of precipitation. The present invention also provides a process for the preparation of such liquid compositions.

FIELD OF THE INVENTION

The present invention relates to stable, room-temperature storable,liquid compositions of posaconazole. The invention further provides aprocess for preparation of the said compositions.

BACKGROUND OF THE INVENTION

Posaconazole is a potent broad-spectrum azole antifungal agent useful inthe treatment of invasive fungal infections. Posaconazole isadministered parenterally for prophylaxis of invasive aspergillus andcandida infections, in patients who are at high risk of developing theseinfections due to being severely immunocompromised such as hematopoieticstem cell transplant recipients with graft-versus-host disease or thosewith hematologic malignancies with prolonged neutropenia fromchemotherapy.

Posaconazole is a weakly basic drug with poor aqueous solubility.Posaconazole is partially solubilized in strong acidic (aqueous)solutions of pH 1 or lower, where it has a solubility of about 790mcg/ml. In contrast, at pH > 4, posaconazole has a solubility of lessthan 1 mcg/ml in aqueous solutions. Although the solubility increasesunder acidic conditions, a more dramatic increase in solubility would berequired to meet the projected daily intravenous dosage of more than 100mg.

Commercially available parenteral posaconazole (NOXAFIL®) is aninjection in the form of a solution containing posaconazole,sulfobutylether beta-cyclodextrin (SBECD), edetate disodium,hydrochloric acid, sodium hydroxide and water for injection. The saidinjection contains posaconazole and SBECD in a weight ratio of 1:22.3.The solution has a pH of around 2.6. The said injection has to be storedat refrigerated conditions of 2-8° C. (36-46° F.).

U.S. Pat. 9,023,790 relates to aqueous solutions of posaconazole forintravenous administration. These compositions containsulfobutylether-beta-cyclodextrin (SBECD) as a solubilizing agent, in anacidified solution, and a chelating agent such as disodium edetate(EDTA). Stability screening studies showed that the said posaconazolesolutions underwent color changes on storage. The development of colorwas minimized by inclusion of EDTA. A storage temperature of 5° C.further minimized the development of yellow color.

Indian Patent Application 4944/MUM/2015 relates to stable parenteralpharmaceutical formulation comprising posaconazole, cyclodextrin,buffering agents and/or pH-adjusting agents and one or more solvents,wherein the pH of the formulation ranges from about 4 to 8. Exemplifiedembodiments of posaconazole solutions (Examples 1, 2), in the saidpatent application, contain posaconazole at a concentration of 18 mg/ml.Other examples are related to freeze dried compositions.

Chinese Patent Publication No. 106265534 relates to a lyophilized powderfor injection comprising posaconazole, a cyclodextrin, a metal ionchelating agent and a pH regulator, and a preparation method thereof.

Chinese Patent No. 103284959 relates to lyophilized powder injection anda preparation method thereof. The powder injection comprises activeingredient posaconazole, a solubilizing cyclodextrin and a pH adjuster,prepared using a process that uses a mix of organic solvents and waterfor injection.

One of the main concerns with posaconazole liquid compositions is thatthey are prone to coloration. According to prior art U.S. Pat. 9,023,790aqueous solutions of posaconazole have been found to become pale yellowcoloured within two weeks of storage at 4° C., 25° C. and 60% RH, and40° C. and 75% RH, the yellow colour growing darker with time.

Another concern with posaconazole liquid compositions is the increasedchances of degradation of the drug when stored at room temperatureconditions, or at accelerated temperature conditions, in accordance withICH guidelines.

Yet another concern with liquid compositions containing a drug such asposaconazole, which has poor and pH-dependent solubility, is theprecipitation of the drug from its liquid composition when diluted withinfusion fluids for parenteral administration.

Commercially available posaconazole parenteral solutions need to bestored at refrigerated conditions of 2-8° C. (36-46° F.) throughouttheir shelf life, to reduce coloration and chemical degradation, and toprevent precipitation.

Maintaining refrigerated conditions during transport and storage ofpharmaceutical products during their shelf life requires cold-chaininfrastructure which can be unreliable, expensive and not feasible.Failure to maintain cold-chain conditions can compromise the quality ofthe product at the point of use.

Further, commercially available posaconazole parenteral solutionscontain stabilizers like EDTA to reduce coloration, and chemicaldegradation. Stabilizers like EDTA have been reported to lead toanaphylactic reactions, kidney damage and kidney failure.

It has surprisingly been found that the liquid compositions ofposaconazole of the present invention exhibit good storage stabilityover extended periods of time at room temperature conditions, withoutthe need for storage at refrigerated conditions. The liquidcompositions, on storage at room temperature conditions, exhibit nosignificant coloration and no significant loss in chemical stability.The liquid compositions also exhibit good dilution stability with noevidence of precipitation.

Thus, the major advantage of the posaconazole liquid compositions of thepresent invention is that it eliminates the need for refrigeration, andspecial handling and/or storage requirements.

Further, the adequate storage stability of the liquid compositions ofposaconazole, at room temperature conditions, can be achieved evenwithout the use of stabilizers.

OBJECTS OF THE INVENTION

The principal object of the present invention is to provide liquidcompositions of posaconazole, the said liquid compositions being stableand storable, at room temperature conditions (i.e. 25° C. ± 2° C., or25° C. ± 2° C. and 60 ± 5% relative humidity, or 30° C. ± 2° C. and 60 ±5% relative humidity).

Another object of the present invention is to provide liquidcompositions of posaconazole, the said liquid compositions being stableand storable at room temperature conditions, with no significantcoloration.

Yet another object of the present invention is to provide stable,room-temperature storable, liquid compositions comprising posaconazole,and hydroxypropyl beta-cyclodextrin.

Yet another object of the present invention is to provide liquidcompositions of posaconazole which are free of stabilizers, the saidliquid compositions being stable and storable, at room temperatureconditions.

Yet another object of the present invention is to provide stable,room-temperature storable, liquid compositions of posaconazole, whichexhibit the desired dilution stability.

Yet another objective of the present invention is to provide liquidcompositions of posaconazole for parenteral administration.

Yet another objective of the present invention is to provide liquidcompositions of posaconazole for parenteral administration, the saidliquid compositions being in the form of a solution.

Yet another objective of the present invention is to provide liquidcompositions of posaconazole for oral administration.

Yet another objective of the present invention is to provide liquidcompositions of posaconazole for oral administration, the said liquidcomposition being in the form of a solution.

Yet another objective is to provide a process for the preparation of thesaid liquid compositions.

SUMMARY OF THE INVENTION

The present invention relates to stable, room-temperature storable,liquid compositions comprising posaconazole. The compositions,preferably in the form of solutions, can be administered orally orparenterally. The present invention also provides a process for thepreparation of such liquid compositions.

DETAILED DESCRIPTION OF THE INVENTION

Chemical degradation, coloration, and precipitation on dilution are themajor challenges in the development of stable liquid compositionscomprising posaconazole, such as posaconazole solutions. Commerciallyavailable posaconazole parenteral solutions need to be stored atrefrigerated conditions of 2-8° C. (36-46° F.) throughout their shelflife, to reduce coloration and chemical degradation, and preventprecipitation on storage and dilution. Further, the solutions requirethe use of stabilizers like EDTA.

It has surprisingly been found that the posaconazole liquid compositionsof the present invention exhibit adequate and desired storage stabilityat room temperature conditions, and do not require refrigerated storageconditions of 2-8° C. (36-46° F.) to achieve the desired shelf life ofat least about 18 months. Further, the said storage stability at roomtemperature conditions can be achieved even without the use of astabilizer like EDTA.

In addition, the said liquid compositions comprising posaconazole, suchas posaconazole solutions, also exhibit desired dilution stability ininfusion fluids, and do not show any precipitation, or render thediluted solution unusable for the desired purpose.

“Room temperature conditions” as used herein refers to 25° C. ± 2° C.,or 25° C. ± 2⁰C and 60% ± 5% relative humidity, or 30° C. ± 2° C. and75% ± 5% relative humidity (RH). Room temperature refers to thetemperature and/or humidity conditions prevailing in a work area, whichrange from 15° C. to 25° C. ± 2° C. and 60% ± 5% relative humidity forMediterranean and subtropical climatic regions (Zone II of the ICHStability Climatic Zone), to 30° C. ± 2° C. and 75% ± 5% relativehumidity for hot and highly humid regions (Zone IVB of the ICH StabilityClimatic Zone). These temperature and/or humidity ranges encompass theusual and customary working environment and temperatures that aregenerally experienced in pharmacies, hospitals, and warehouses, andduring shipping, in these regions. ICH guidelines recommend conductinglong-term storage stability studies at the “room temperature conditions”of the various zones to establish its stability and shelf-life.

“Room temperature storable” when used herein refers to liquidcomposition that can be stored at “room temperature” for at least aperiod of 6 months, without significant coloration, and withoutsignificant loss of chemical stability.

“Accelerated temperature conditions” as used herein refers to 40° C. ±2⁰C and 75% ± 5% relative humidity.

The degree of coloration of liquid compositions of posaconazole isdetermined using European Pharmacopeia (EP) Color Standards. Thesestandards are visual color standards, intended to define a sample coloras being close to a physical liquid standard (2.2.2 Degree of Colorationof Liquids, European Pharmacopoeia). The test is carried out bycomparing the test solution with a standard color solution, when vieweddown the vertical axis of the tubes, in diffused light, against a whitebackground. In the present invention, EP Color Standard BY(brownish-yellow) solutions are used as a reference to determine thecoloration of posaconazole liquid compositions.

“Coloration” as used herein means a degree of coloration more intensethan BY4, preferably more intense than BY5, and more preferably moreintense than BY6.

“Chemical stability” as used herein means that the content ofposaconazole, as determined by an HPLC assay method, is not less than90% of the label claim, and the percent total impurities, as determinedby an HPLC method, is not more than 2%.

The liquid compositions of posaconazole can be in the form of solutions,suspensions, colloids, or emulsions. Preferably, the liquid compositionsof posaconazole are in the form of a solution.

In an aspect of the invention, the liquid compositions may be driedusing processes such as spray-drying, fluid bed drying, or freeze drying(lyophilisation) to provide powders. The said powder can bereconstituted with liquid vehicles to provide solutions, suspensions,colloids, or emulsions.

The liquid compositions of posaconazole, of the present invention, canbe administered orally or parenterally.

The room temperature storable liquid compositions of posaconazole of thepresent invention exhibit the desired chemical stability and nocoloration, when stored at room temperature conditions over extendedperiods of time.

In one aspect, the posaconazole liquid composition of the presentinvention is stable at room temperature conditions for at least 18months.

In another aspect, the room temperature storable liquid compositions ofposaconazole, comprise posaconazole, hydroxypropyl beta-cyclodextrin(HPBCD), and a vehicle.

In another aspect, the room temperature storable liquid compositions ofposaconazole, consist essentially of posaconazole, hydroxypropylbeta-cyclodextrin, and a vehicle.

In another aspect, the room temperature storable liquid compositionscomprise posaconazole, hydroxypropyl beta-cyclodextrin, and water as thevehicle.

In another aspect, the room temperature storable liquid compositionscomprise posaconazole, hydroxypropyl beta-cyclodextrin, sodium edetate,and water as the vehicle.

In another aspect, the room temperature storable liquid compositionscomprise posaconazole, hydroxypropyl beta-cyclodextrin, sodium edetate,and water as the vehicle.

In yet another aspect, the room temperature storable liquid compositionscomprise posaconazole, hydroxypropyl beta-cyclodextrin, and a vehicle,the said liquid compositions being free of stabilizers.

Liquid compositions of posaconazole contain posaconazole inconcentrations ranging from about 10 mg/ml to about 30 mg/ml, preferablyfrom about 15 mg/ml to about 30 mg/ml, and more preferably from about 18mg/ml to about 30 mg/ml of the said liquid composition.

Liquid compositions of posaconazole contain about 1.0%w/v to about3.0%w/v, preferably about 1.5%w/v to about 3.0%w/v, and more preferablyabout 1.8%w/v to about 3.0%w/v of posaconazole.

Liquid compositions of posaconazole comprise hydroxypropylbeta-cyclodextrin in concentrations ranging from about 100 mg/ml toabout 500 mg/ml, preferably from about 150 mg/ml to about 450 mg/ml, andmore preferably from about 200 mg/ml to about 400 mg/ml, and mostpreferably from about 250 mg/ml to about 350 mg/ml, of the said liquidcomposition.

In one aspect, the said liquid compositions comprise posaconazole andhydroxypropyl beta-cyclodextrin, in a weight ratio ranging from about1:5 to about 1:30, preferably from about 1:5 to about 1:25 and morepreferably from about 1:10 to about 1:25.

In another aspect, the said liquid compositions comprise posaconazoleand hydroxypropyl beta-cyclodextrin, in a molar ratio ranging from about1:5 to about 1:25, preferably from about 1:5 to about 1:20 and morepreferably from about 1:5 to about 1:15.

One or more vehicles in the liquid compositions of posaconazole areselected from aqueous vehicles such as water for injection, alcohols(such as ethyl alcohol), glycols (such as propylene glycol, butyleneglycol, glycerol, polyethylene glycol), dioxalanes, dimethylacetamide,hydroxyethyl lactamide, dimethylsulfoxide, and non-aqueous vehicles likepolyoxyethylated castor oils, oils (such as corn oil, cottonseed oil,sesame oil, peanut oil), fixed oils, ethyl oleate, isopropyl myristate,and benzyl benzoate. Preferably, the vehicle in the posaconazole liquidcompositions of the present invention is water for injection.

Posaconazole liquid compositions may further comprise excipientsselected from anti-oxidants, chelating agents, pH-adjusting agents,buffering agents, and tonicity agents.

Anti-oxidants are selected from those known in the art such as butylatedhydroxyanisole, butylated hydroxytoluene, propyl gallate, sodiummetabisulfite, sodium sulfite, sodium bisulfite, citric acid, ascorbicacid or mixtures thereof.

Chelating agents are selected from those known in the art such asethylenediaminetetraacetic acid (EDTA), ethylenediamine-N,N′-diacetic-N, N′-dipropionic acid, diethylenetriaminepentaacetic acid(DTPA), ethylene glycol-bis(beta-aminoethyl ether)- tetraacetic acid(EGTA), N-(hydroxy ethyl) ethylenediaminetriacetic acid (HEDTA), andnitrilotriacetic acid (NTA), or salts thereof. The term EDTA as usedherein includes ethylenediaminetetraacetic acid, its salts, hydrates,solvates and derivatives, such as disodium ethylenediaminetetraaceticacid (disodium edetate), disodium ethylenediaminetetraacetic aciddihydrate (disodium edetate dihydrate), sodium calciumethylenediaminetetraacetic acid (sodium calcium edetate), andtetrasodium ethylenediaminetetraacetic acid (tetrasodium edetate). In anaspect, chelating agents such as EDTA act as stabilizers and preventcoloration of posaconazole liquid compositions.

pH-adjusting agents can be acid or base. The base can be oxides,hydroxides, carbonates, bicarbonates and the like. The oxides can bemetal oxides such as calcium oxide, and magnesium oxide; hydroxides canbe of alkali metals and alkaline earth metals such as sodium hydroxide,potassium hydroxide, and calcium hydroxide; and carbonates can be sodiumcarbonate, sodium bicarbonates, and potassium bicarbonates. The acid canbe mineral acids or organic acids such as hydrochloric, nitric,phosphoric, acetic, citric, sulfuric, fumaric, maleic, malic, tartaric,methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, lactic,ascorbic acid, and glycine hydrochloride.

Buffering agents are selected from those known in the art and can becitrates, acetates, phosphates, other organic buffers and the like.

Tonicity agents are selected from those known in the art and can beselected from ionic tonicity agents such as sodium chloride, potassiumchloride, magnesium chloride or calcium chloride, or non-ionic tonicityagents such as glycerine, dextrose and mannitol.

pH of the posaconazole liquid compositions can range from pH 2 to pH 4,preferably from pH 2.5 to pH 3.5, more preferably from pH 2.8 to pH 3.2.

Posaconazole liquid compositions of the present invention are stable andstorable at room temperature conditions for extended periods of time,with no coloration, and no significant chemical degradation. The saidliquid compositions do not require refrigerated conditions for storage.

Storage stability of the liquid compositions of the present inventionwas evaluated by subjecting the liquid compositions to storage at thefollowing conditions for various time periods:

-   Room temperature conditions: 25° C. ± 2° C., or 25° C. ± 2° C. and    60% ± 5% RH, or 30° C. ± 2° C. and 75% ± 5% RH,-   Accelerated temperature conditions: 40° C. ± 2° C. and 75% ± 5% RH

The compositions were analyzed for posaconazole content, percent knownimpurity (hydroxy triazole, deshydroxy posaconazole, benzylatedposaconazole), and percent total impurities, after the time period.

In one aspect of the invention, the content of posaconazole in theliquid compositions, after storage at room temperature conditions for atleast 3 months, is not less than 90%, preferably not less than 95% andmore preferably not less than 98% of the label claim.

In another aspect of the invention, the content of posaconazole in theliquid compositions, after storage at room temperature conditions, forat least 6 months, is not less than 90%, preferably not less than 95%and more preferably not less than 98% of the label claim.

In another aspect of the invention, the content of posaconazole in theliquid compositions, after storage at room temperature conditions, forat least 12 months, is not less than 90%, preferably not less than 95%and more preferably not less than 98% of the label claim.

In another aspect of the invention, the content of posaconazole in theliquid compositions, after storage at room temperature conditions, forat least 18 months, is not less than 90%, preferably not less than 95%and more preferably not less than 98% of the label claim.

In another aspect of the invention, the content of posaconazole in theliquid compositions, after storage at room temperature conditions, forat least 22 months, is not less than 90%, preferably not less than 95%and more preferably not less than 98% of the label claim.

In another aspect of the invention, the content of posaconazole in theliquid compositions, after storage at room temperature conditions, forat least 24 months, is not less than 90%, preferably not less than 95%and more preferably not less than 98% of the label claim.

In yet another aspect of the invention, the content of posaconazole inthe liquid compositions, after storage at accelerated temperatureconditions, for at least 3 months, is not less than 90%, preferably notless than 95% and more preferably not less than 98% of the label claim.

In yet another aspect of the invention, the content of posaconazole inthe liquid compositions, after storage at accelerated temperatureconditions for at least 6 months, is not less than 90%, preferably notless than 95% and more preferably not less than 98% of the label claim.

In one aspect of the invention, the known impurity (hydroxy triazole,deshydroxy posaconazole, or benzylated posaconazole) in the liquidcomposition, after storage at room temperature conditions for at least18 months, or accelerated temperature conditions for at least 6 months,is not more than 0.5%, preferably not more than 0.3% and more preferablynot more than 0.2%.

In another aspect of the invention, the total impurities in the liquidcomposition, after storage at room temperature conditions for at least18 months, or accelerated temperature conditions for at least 6 months,is not more than 2%, preferably not more than 1.5% and more preferablynot more than 1%.

In an embodiment, the total impurities in the liquid composition, afterstorage at room temperature conditions, for at least 18 months, is notmore than 0.8%.

In another embodiment, the total impurities in the liquid composition,after storage at room temperature conditions, for at least 18 months, isnot more than 0.5%.

In one aspect the posaconazole liquid compositions for parenteraladministration, when filled in vials, are chemically stable afterstorage in the upright orientation, at room temperature conditions, oraccelerated temperature conditions, for various time periods asdiscussed above.

In another aspect the posaconazole liquid compositions for parenteraladministration, when filled in vials, are chemically stable afterstorage in the inverted orientation, at room temperature conditions, oraccelerated temperature conditions, for various time periods asdiscussed above.

Posaconazole liquid compositions of the present invention exhibit nocoloration at room temperature conditions, after storage for extendedperiods of time for at least up to about 18 months.

In one aspect of the invention, the posaconazole liquid compositions ofthe present invention, show a coloration not more intense than BY6 afterstorage at room temperature conditions for at least 3 months.

In another aspect, the posaconazole liquid compositions of the presentinvention, show a coloration not more intense than BY6, after storage atroom temperature conditions for at least 6 months.

In another aspect, the posaconazole liquid compositions of the presentinvention, show a coloration not more intense than BY5, after storage atroom temperature conditions for at least 18 months.

In another aspect, the posaconazole liquid compositions of the presentinvention, show a coloration not more intense than BY4, after storage atroom temperature conditions for at least 20 months.

In another aspect of the invention, the posaconazole liquid compositionsof the present invention, show a coloration not more intense than BY6after 3 months of storage at accelerated temperature conditions.

In another aspect of the invention, the posaconazole liquid compositionsof the present invention, show a coloration not more intense than BY4after 6 months of storage at accelerated temperature conditions.

Compositions of posaconazole in the form of solutions, for parenteraladministration to a patient, may have to be aseptically diluted with asuitable infusion fluids before administration. Compositions on dilutionwith infusion fluids, are prone to precipitation of posaconazole fromthe composition, as posaconazole is a drug having poor and pH-dependentsolubility.

In one aspect, the liquid compositions of posaconazole for parenteraladministration are stable to dilution. The said solutions, afterdilution with infusion fluids, are clear and do not show precipitationor turbidity for at least 24 hours, preferably at least 48 hours. Theposaconazole solutions are stable to dilution ratios of upto about 1:30,preferably upto about 1:25, more preferably upto about 1:20 in infusionfluids.

Suitable infusion fluids are selected from those known in the art suchas 5% dextrose solution in water, 0.45% sodium chloride solution inwater, 0.9% sodium chloride solution in water, 5% dextrose and 0.45%sodium chloride solution in water, 5% dextrose and 0.9% sodium chloridesolution in water and 5% dextrose and 20 mEq potassium chloride solutionin water.

Liquid compositions of posaconazole, in the form of solutions forparenteral administration, were evaluated for tonicity using a FreezingPoint Osmometer (Osmomat 3000) using 0.9% sodium chloride solution asthe standard. Commercially available posaconazole parenteral solutionsexhibit hyper-tonicity, with an osmolality greater than 2000 mOsmol/kg.Hence, commercially available posaconazole parenteral solutions have tobe administered after dilution in infusion liquids, and cannot beadministered as an intravenous bolus injection.

In an aspect, posaconazole liquid compositions of the present inventionhave an osmolality ranging from about 200 mOsmol/kg to about 800mOsmol/kg, preferably from 200 mOsmol/kg to about 700 mOsmol/kg, morepreferably from 200 mOsmol/kg to about 600 mOsmol/kg, and mostpreferably from 200 mOsmol/kg to about 500 mOsmol/kg.

In an aspect, posaconazole liquid compositions of the present inventionhaving an osmolality ranging from about 200 mOsmol/kg to about 500mOsmol/kg, can be injected as a bolus without dilution with infusionfluids.

In an embodiment, the liquid composition comprising posaconazole,hydroxypropyl beta-cyclodextrin and a vehicle, is stable atroom-temperature for at least 18 months, preferably for at least 20months, more preferably for at least 22 months, and most preferably forat least 24 months.

In another embodiment, the liquid composition comprising posaconazole,hydroxypropyl beta-cyclodextrin, and water as a vehicle, is stable atroom-temperature for at least 18 months, preferably for at least 20months, more preferably for at least 22 months, and most preferably forat least 24 months.

In yet another embodiment, the liquid composition comprisingposaconazole, hydroxypropyl beta-cyclodextrin and water as a vehicle, isfree of stabilizers, and is stable at room-temperature for at least 18months, preferably for at least 20 months, more preferably for at least22 months, and most preferably for at least 24 months.

In an aspect, the liquid compositions comprising posaconazole, have aroom temperature shelf-life of at least 18 months, preferably of atleast 20 months, more preferably of at least 22 months and mostpreferably of at least 24 months.

In another aspect, the liquid compositions comprising posaconazole, havea room temperature shelf-life of at least 24 months, in accordance withICH guidelines.

In an embodiment, the liquid composition for parenteral administration,comprising posaconazole, is stable at room temperature conditions for atleast 18 months, preferably for at least 20 months, more preferably forat least 22 months, and most preferably for at least 24 months.

In another embodiment, the liquid composition for parenteraladministration, comprising posaconazole and hydroxypropylbeta-cyclodextrin, is stable at room temperature conditions for at least18 months, preferably for at least 20 months, more preferably for atleast 22 months, and most preferably for at least 24 months.

In yet another embodiment, the liquid composition for parenteraladministration, comprising posaconazole, hydroxypropyl beta-cyclodextrinand a vehicle, is stable at room temperature conditions for at least 18months, preferably for at least 20 months, more preferably for at least22 months, and most preferably for at least 24 months.

In an embodiment, the room-temperature storable liquid compositioncomprises posaconazole, hydroxypropyl beta-cyclodextrin, and at leastone vehicle.

In another embodiment, the room-temperature storable liquid compositioncomprises posaconazole, hydroxypropyl beta-cyclodextrin, and water asthe vehicle.

In yet another embodiment, the room-temperature storable liquidcomposition, comprising posaconazole, hydroxypropyl beta-cyclodextrin,and water as the vehicle, is free of stabilizers

The present invention also deals with a method of stabilizingposaconazole liquid composition, wherein the method comprises dissolvingposaconazole in HPBCD solution, and adjusting the pH of theposaconazole-HPBCD solution to about 2 to 4, and wherein theposaconazole liquid composition is stable at room temperature conditionsfor at least 18 months.

The liquid compositions of posaconazole of the present invention areprepared by processes such as dissolving/dispersing posaconazole, HPBCDand/or other excipients in a vehicle, homogenization, adjusting the pHusing pH-adjusting agents, sparging liquid with non-oxygen containinggas, adding vehicle to obtain the final volume, filtering the liquidcomposition, filling the liquid composition in a container, sealing thecontainer, and/or sterilizing the liquid composition.

Processes for the preparation of liquid compositions of posaconazole forparenteral administration is preferably carried out under an overlay ofa non-oxygen containing gas such as nitrogen.

In one of the embodiments of the present invention, the posaconazoleliquid composition is prepared by a process comprising steps of:

-   (i) sparging water with a non-oxygen containing gas;-   (ii) dissolving HPBCD, and at least one optional excipients selected    from anti-oxidants, chelating agents, pH-adjusting agents, buffering    agents and/or tonicity agents, in water sparged with non-oxygen    containing gas, to obtain a HPBCD solution;-   (iii) acidifying HPBCD solution to pH 1 - 2 using hydrochloric acid;-   (iv) dissolving posaconazole in acidified HPBCD solution, to obtain    a posaconazole solution;-   (v) adjusting the pH of the posaconazole solution to pH 2 - 4 by    adding sodium hydroxide and/or hydrochloric acid;-   (vi) adding water to posaconazole solution and mixing it, to obtain    the final batch volume, wherein the process steps (ii) to (vi) are    carried out under an overlay of a non-oxygen containing gas.

In another embodiment, the posaconazole liquid composition is processedusing one or more of the following steps:

-   (i) posaconazole liquid composition is filtered through a filter-   (ii) posaconazole liquid composition is filled in containers-   (iii) headspace of the container is overlayed with a non-oxygen    containing gas-   (iv) the container is capped-   (v) the container is sealed

In another embodiment, liquid composition of posaconazole, in the formof a solution, was prepared using the following manufacturing process:

HPBCD, and optionally excipients selected from anti-oxidants, chelatingagents, pH-adjusting agents, buffering agents and/or tonicity agents,was added to and dissolved in water (sparged with nitrogen) to provide aclear HPBCD solution. HPBCD solution was acidified to pH 1 - 2 usinghydrochloric acid. Posaconazole was added and dissolved in the acidifiedHPBCD solution to obtain a clear posaconazole solution. Additionalsodium hydroxide or hydrochloric acid was added to the solution toadjust the pH of the posaconazole solution to pH 2 - 4. Water was addedto obtain the final volume. The process of preparation of the solutionwas carried out under nitrogen overlay.

Liquid compositions of posaconazole, for parenteral administration, canbe sterilized by dry heat sterilization, moist heat sterilization,chemical sterilization, radiation sterilization, and filtrationsterilization. Filtration sterilization is one of the preferred methodsof sterilization, as the method provides liquid compositions ofposaconazole with the lowest degree of coloration, when compared toliquid compositions subjected to moist heat sterilization.

Filter materials used in the sterilization of liquid compositionsinclude but are not limited to nylon, polycarbonate, cellulose acetate,polyvinylidene fluoride (PVDF), and polyethersulfone (PES). Pore sizesof the filters may range from 0.1 microns to 5 microns.

Liquid compositions of posaconazole are filled in containers whichinclude vials, bottles, ampoules, cartridges, flexible bags andpre-filled syringes. The said containers maybe made of glass or plastic,or any other suitable material.

The invention is now illustrated with non - limiting examples.

Example 1

Disodium ethylene diamine tetraacetic acid dihydrate (sodium edetate)(0.18 g) was dissolved in 450 ml of water (sparged with nitrogen) understirring. HPBCD (380.0 g) was added to the sodium edetate solution andcontinuously stirred till a clear solution was obtained. The pH wasadjusted to about 1.5-2.0 using hydrochloric acid. Posaconazole (18.0 g)was added to the sodium edetate - cyclodextrin solution and continuouslystirred till a clear solution was obtained. The pH was adjusted to about2.3-2.8 using sodium hydroxide or hydrochloric acid. Water (sparged withnitrogen) was added to obtain the final volume (1000 ml), and mixed toobtain a posaconazole liquid solution. The process of preparation of thesolution was carried out under nitrogen overlay.

The solution was filtered through 0.22 micron PVDF filter, and filled insterilized vials (10 ml USP Type 1 Fiolax clear glass vial). The vialheadspace was overlayed with nitrogen, the vials stoppered using 20 mmbromobutyl fluorocarbon coated rubber stopper and sealed using 20 mmaluminium flip-off seals having PP disc.

Example 2

HPBCD (380.0 g) was added to 450 ml of water (sparged with nitrogen) andstirred continuously, optionally heating it to 65° C., till a clearsolution was obtained. Posaconazole (18.0 g) was added to thecyclodextrin solution, with optional heating to 70° C., and continuousstirring. The pH was adjusted to about 2.4 - 2.7 using hydrochloricacid. Water (sparged with nitrogen) was added to obtain the final volume(1000 ml), and mixed to obtain a posaconazole liquid solution. Theprocess of preparation of the solution was carried out under nitrogenoverlay.

The solution was filtered through 0.22 micron PVDF filter, and filled insterilized vials (10 ml USP Type 1 Fiolax clear glass vial). The vialheadspace was overlayed with nitrogen, the vials stoppered using 20 mmbromobutyl fluorocarbon coated rubber stopper and sealed using 20 mmaluminium flip-off seals having PP disc.

Example 3

Disodium ethylene diamine tetraacetic acid dihydrate (sodium edetate)(0.18 g) was dissolved in 450 ml of water (sparged with nitrogen) understirring. HPBCD (280.0 g) was added to the sodium edetate solution andstirred continuously till a clear solution was obtained. The pH wasadjusted to about 1.6 - 1.9 using hydrochloric acid. Posaconazole (18.0g) was added to the sodium edetate - HPBCD solution, and stirredcontinuously till a clear solution was obtained. The pH was adjusted toabout 2.4 - 2.6 using sodium hydroxide or hydrochloric acid. Water(sparged with nitrogen) was added to obtain the final volume (1000 ml),and mixed, to obtain a posaconazole liquid solution. The process ofpreparation of the solution was carried out under nitrogen overlay.

The solution was filtered through 0.22 micron PVDF filter, and filled insterilized vials (10 ml USP Type 1 Fiolax clear glass vial) at a fillvolume of 16.7 ml. The vial headspace was overlayed with nitrogen, thevials stoppered using 20 mm bromobutyl fluorocarbon coated rubberstopper and sealed using 20 mm aluminium flip-off seals having PP disc.

Example 4

HPBCD (200.0 g) was added to 450 ml of water and continuously stirredtill a clear solution was obtained. Tartaric acid (9.0 g) was added tothe cyclodextrin solution. The pH was adjusted to about 1.6 using sodiumhydroxide or hydrochloric acid. Posaconazole (10.0 g) was added to theHPBCD - tartaric acid solution and continuously stirred till a clearsolution was obtained. The pH was adjusted to about 2.4 using sodiumhydroxide or hydrochloric acid. Water was added to obtain the finalvolume (1000 ml), and mixed to obtain a posaconazole liquid solution.The process of preparation of the solution was carried out undernitrogen overlay.

The solution was filtered through 0.22 micron PVDF filter, and filled insterilized vials (10 ml USP Type 1 Fiolax clear glass vial). The vialheadspace was overlayed with nitrogen, the vials stoppered using 20 mmbromobutyl fluorocarbon coated rubber stopper and sealed using 20 mmaluminium flip-off seals having PP disc.

EVALUATION OF POSACONAZOLE LIQUID COMPOSITIONS Degree of Coloration

Table 1 provides a comparison of the degree of coloration of aqueoussolutions of commercially available posaconazole parenteral solutionproduct, and posaconazole liquid compositions of examples 1, 3 and 4,after the said solutions were stored at room temperature conditions. Thecomparison was done using EP Color Standards of BY range.

TABLE 1 Degree of coloration of the commercially available product andposaconazole solutions of examples 1, 3 and 4 Sample Degree ofColoration Commercially available product 0 months More intense than BY66 months (25° C. ± 2° C. / 60% ± 5%RH) More intense than BY5 Example 1 0month Not more intense than BY7 6 months (25° C. ± 2° C. / 60% ± 5%RH)Not more intense than BY6 6 months (30° C. ± 2° C. / 75% ± 5%RH) Notmore intense than BY6 Example 3 0 month Not more intense than BY7 22months (25° C. ± 2° C.) Not more intense than BY5 Example 4 0 month Notmore intense than BY7 1 month (25° C. ± 2° C. / 60% ± 5%RH) Not moreintense than BY7

Chemical Stability

The chemical stability of posaconazole liquid compositions of examples1, 2, and 3, on storage (upright and inverted positions) at roomtemperature conditions was studied by determining the posaconazolecontent and percent impurities of the liquid composition. The resultsare given in Tables 2, 3 and 4.

TABLE 2 Posaconazole content and % impurities of liquid compositions ofexample 1 after storage at room temperature conditions Example 1 RoomTemperature Conditions (25° C. ± 2° C. / 60% ± 5%RH) EvaluationParameter Time-period of storage Initial 1 M ↑ 3 M ↑ 3 M ↓ 6 M ↑ 6 M ↓ %Assay 102.2 99.8 100.3 99.0 102.5 102.2 % Hydroxy Triazole ND ND ND NDND ND % Deshydroxy Posaconazole ND ND 0.04 0.04 0.04 0.04 % BenzylatedPosaconazole ND ND 0.02 0.03 0.02 0.03 % Total Impurities 0.14 0.07 0.260.27 0.12 0.13 Room Temperature Conditions (30° C. ± 2° C. / 75% ± 5%RH)Evaluation Parameter Time-period of storage Initial 1 M ↑ 3 M ↑ 3 M ↓ 6M ↑ 6 M ↓ % Assay 102.2 97.4 98.2 98.6 101.8 100.9 % Hydroxy Triazole NDND ND ND ND ND % Deshydroxy Posaconazole ND ND 0.05 0.04 0.05 0.04 %Benzylated Posaconazole ND ND 0.02 0.02 0.03 0.03 % Total Impurities0.14 0.07 0.29 0.28 0.13 0.17 ND =Not Detected; M =Month(s); ‘↑’=Upright Orientation of vial; ‘↓’ =Inverted Orientation of vial

TABLE 3 Posaconazole content and % impurities of liquid compositions ofexample 2 after storage at room temperature conditions Example 2 RoomTemperature Conditions (25° C. ± 2° C. and 60% ± 5%RH) EvaluationParameter Time-period of storage Initial 1 M ↑ 3 M ↑ 6 M ↑ % Assay 98.0101.6 100.4 100.5 % Hydroxy Triazole ND ND ND ND % DeshydroxyPosaconazole 0.03 ND 0.02 0.03 % Benzylated Posaconazole 0.02 ND 0.020.03 % Total Impurities 0.05 0.18 0.07 0.33 ND =Not Detected; M=Month(s); ‘↑’ =Upright Orientation of vial; ‘↓’ =Inverted Orientationof vial

TABLE 4 Posaconazole content and % impurities of liquid compositions ofexample 3 after storage at room temperature conditions Example 3 RoomTemperature Conditions (25° C. ± 2° C. and 60% ± 5%RH) EvaluationParameter Time Period of Storage Initial 3 M ↑ 3 M ↓ 6 M ↑ 6 M ↓ % Assay100.3 99.3 101.6 99.3 101.6 % Hydroxy Triazole ND ND ND ND ND %Deshydroxy Posaconazole ND 0.01 0.01 0.01 0.01 % Benzylated PosaconazoleND ND ND ND ND % Total Impurities 0.10 0.26 0.27 0.23 0.24 RoomTemperature Conditions (30° C. ± 2° C. and 75% ± 5%RH) EvaluationParameter Time Period of Storage Initial 3 M ↑ 3 M ↓ 6 M ↑ 6 M ↓ % Assay100.3 98.7 99.4 102.4 103.0 % Hydroxy Triazole ND ND ND ND ND %Deshydroxy Posaconazole ND 0.01 0.01 0.01 0.01 % Benzylated PosaconazoleND ND ND ND ND % Total Impurities 0.10 0.27 0.27 0.26 0.25 RoomTemperature Conditions (25° C. ± 2° C.) Evaluation Parameter Time Periodof Storage Inital 22 M ↑ 22 M ↓ % Assay 100.3 101.3 103.0 % HydroxyTriazole ND ND ND % Deshydroxy Posaconazole ND 0.01 0.01 % BenzylatedPosaconazole ND ND ND % Total Impurities 0.10 0.33 0.36 ND =NotDetected; M =Month(s); ‘↑’ =Upright Orientation of vial; ‘↓’ =InvertedOrientation of vial

The chemical stability of posaconazole liquid compositions of examples1, 2, and 3, after storage (upright and inverted positions) ataccelerated conditions was studied by determining the posaconazolecontent and percent impurities of the compositions. The results aregiven in Table 5, 6 and 7.

TABLE 5 Posaconazole content and % impurities of liquid compositions ofExample 1 after storage at accelerated temperature conditions Example 1Accelerated Temperature Conditions (40° C. ± 2° C. and 75% ± 5%RH)Evaluation Parameter Time Period of Storage Initial 1 M ↑ 1 M ↓ 3 M ↑ 3M ↓ 6 M ↑ 6 M ↓ % Assay 102.2 100.4 96.3 101.9 101.8 98.4 96.9 % HydroxyTriazole ND ND ND ND ND ND ND % Deshydroxy Posaconazole ND ND ND 0.040.04 0.04 0.05 % Benzylated Posaconazole ND ND ND 0.02 0.02 0.03 0.03 %Total Impurities 0.14 0.11 0.11 0.41 0.42 0.37 0.43 ND =Not Detected; M=Month(s); ‘↑’ =Upright Orientation of vial; ‘↓’ =Inverted Orientationof vial

TABLE 6 Posaconazole content and % impurities of liquid compositions ofExample 2 after storage at accelerated temperature conditions Example 2Accelerated Temperature Conditions (40° C. ± 2° C. / 75% ± 5%RH)Evaluation Parameter Time Period of Storage Initial 1 M ↑ 3 M ↑ 6 M ↓ %Assay 98.0 98.5 101.0 100.2 % Hydroxy Triazole ND ND ND 0.02 %Deshydroxy Posaconazole 0.03 ND 0.02 0.03 % Benzylated Posaconazole 0.02ND 0.02 0.02 % Total Impurities 0.05 0.50 0.36 1.17 ND =Not Detected; M=Month(s); ‘↑’ =Upright Orientation of vial; ‘↓’ =Inverted Orientationof vial

TABLE 7 Posaconazole content and % impurities of liquid compositions ofExample 3 after storage at accelerated temperature conditions Example 3Accelerated Temperature (40° C. ± 2° C. and 75% ± 5%RH) EvaluationParameter Time Period of Storage Initial 1 M ↑ 1 M ↓ 3 M ↑ 3 M ↓ 6 M ↑ 6M ↓ % Assay 100.3 100.8 100.8 99.6 100.9 99.6 100.9 % Hydroxy TriazoleND ND ND ND ND ND ND % Deshydroxy Posaconazole ND ND ND 0.01 0.01 0.010.01 % Benzylated Posaconazole ND ND ND ND ND ND ND % Total Impurities0.10 0.26 0.27 0.37 0.38 0.50 0.41 ND =Not Detected; M =Month(s); ‘↑’=Upright Orientation of vial; ‘↓’ =Inverted Orientation of vial

Dilution Studies and Tonicity

Posaconazole liquid compositions of Examples 1, 2, 3 and 4 were dilutedto a dilution ratio of 1:17 by mixing 1 ml of the liquid composition ofthe example and 17 ml of 0.9% sodium chloride solution in water. Noprecipitation or turbidity was observed in the diluted solution onstorage at room temperature for 24 to 48 hours.

Posaconazole liquid compositions of Examples 1, 2, 3 and 4 were dilutedto a dilution ratio of 1:17 by mixing 1 ml of the liquid composition ofthe example and 17 ml of 5% dextrose solution in water. No precipitationor turbidity was observed in the diluted solution on storage at roomtemperature for about 24 to about 48 hours.

The osmolality of the liquid compositions of Examples 1, 2 and 3 weredetermined to be 670 mOsmol/kg, 608 mOsmol/kg and 340 mOsmol/kgrespectively, while the osmolality of the commercially availableposaconazole solution for injection was found to be 2355 mOsmol/kg.

Thus, it has surprisingly been found that posaconazole liquidcompositions of the present invention are room temperature storable. Thesaid solutions exhibit good chemical stability and show no significantcoloration, when stored at room temperature conditions for extendedperiods of time. The said liquid compositions of posaconazole exhibitgood dilution stability, and exhibit an osmolality of about 200mOsmol/kg to about 800 mOsmol/kg. The posaconazole liquid compositionscomprise hydroxypropyl beta-cyclodextrin and a vehicle. Further, thesaid compositions are room temperature storable even without theinclusion of a stabilizer like EDTA.

We claim: 1-22. (canceled)
 23. A posaconazole liquid composition,comprising i posaconazole at a concentration of about 15 mg/ml to about30 mg/ml in the composition, ii hydroxypropyl beta-cyclodextrin, and iiia vehicle, and wherein the composition is stable at a temperature ofabout 20⁰C to about 32⁰C for at least 18 months.
 24. The posaconazoleliquid composition as claimed in claim 23, wherein the concentration ofhydroxypropyl beta-cyclodextrin in the composition ranges from about 100mg/ml to about 500 mg/ml.
 25. The posaconazole liquid composition asclaimed in claim 23, wherein the vehicle is water.
 26. The posaconazoleliquid composition as claimed in claim 23, wherein the compositionfurther comprises at least one excipient selected from anti-oxidants,chelating agents, pH-adjusting agents, buffering agents or tonicityagents.
 27. The posaconazole liquid composition as claimed in claim 26,wherein the chelating agent is sodium edetate.
 28. The posaconazoleliquid composition as claimed in claim 23, wherein the composition is inthe form of a solution for parenteral administration.
 29. Theposaconazole liquid composition as claimed in claim 23, wherein thecomposition shows a coloration not more intense than BY6 at the end ofabout 6 months of storage at a temperature of about 20⁰C to about 32⁰Cand a relative humidity of about 55% to about 80%.
 30. The posaconazoleliquid composition as claimed in claim 23, wherein the composition isstable to dilution when 1 part of the posaconazole liquid composition isdiluted to about 30 parts by infusion fluids.
 31. The posaconazoleliquid composition as claimed in claim 23, wherein the osmolality of thecomposition ranges from about 200 mOsmol/kg to about 800 mOsmol/kg. 32.The posaconazole liquid composition as claimed in claim 23, wherein thecomposition when stored at a temperature of about 20° C. to about 32°C., for at least 22 months, in an upright orientation or invertedorientation, contains posaconazole not less than about 90% by weight ofthe label claim and contains not more than about 2% by weight of totalimpurities, at the end of the given storage period.
 33. A process forthe preparation of posaconazole liquid composition wherein the processcomprises steps of: (i) sparging vehicle with a non-oxygen containinggas, (ii) dissolving hydroxypropyl beta-cyclodextrin, and one or moreoptional excipients selected from anti-oxidants, chelating agents,pH-adjusting agents, buffering agents and/or tonicity agents, in vehiclesparged with non-oxygen containing gas, to obtain a hydroxypropylbeta-cyclodextrin solution, (iii) acidifying hydroxypropylbeta-cyclodextrin solution to about pH 1 to about pH 2 usinghydrochloric acid, (iv) dissolving posaconazole in acidifiedhydroxypropyl beta-cyclodextrin solution, to obtain a posaconazolesolution, (v) adjusting the pH of the posaconazole solution to about pH2 to about pH 4 by adding sodium hydroxide and/or hydrochloric acid, and(vi) adding vehicle to posaconazole solution and mixing it, to obtainthe final batch volume; wherein the process steps (ii) to (vi) arecarried out under an overlay of a non-oxygen containing gas.
 34. Theprocess as claimed in claim 33, wherein the concentration ofposaconazole in the composition ranges from about 10 mg/ml to about 30mg/ml.
 35. The process as claimed in claim 33, wherein the concentrationof hydroxypropyl beta-cyclodextrin in the composition ranges from about100 mg/ml to about 500 mg/ml.
 36. The process as claimed in claim 33,wherein the vehicle is water.
 37. The process as claimed in claim 33,wherein the composition is in the form of a solution for parenteraladministration.
 38. A method of preparing a stable posaconazole liquidcomposition comprising preparing a solution of hydroxypropylbeta-cyclodextrin in a vehicle, dissolving posaconazole in thehydroxypropyl beta-cyclodextrin solution, and adjusting the pH of theposaconazole-hydroxypropyl beta-cyclodextrin solution to about pH 2 toabout pH 4, wherein the concentration of posaconazole in the compositionis about 15 mg/ml to about 30 mg/ml, and wherein the composition isstable at a temperature of about 20⁰C to about 32⁰C for at least 24months.
 39. The method as claimed in claim 38, wherein the posaconazoleliquid composition shows a coloration not more intense than BY6 at theend of about 6 months of storage at a temperature of about 20° C. toabout 32° C. and a relative humidity of about 55% to about 80%.
 40. Themethod as claimed in claim 38, wherein the composition is stable todilution when 1 part of the posaconazole liquid composition is dilutedto about 30 parts by infusion fluids.
 41. The method as claimed in claim38, wherein the posaconazole liquid composition, when stored in vials inan upright orientation or inverted orientation, contains posaconazolenot less than about 95% by weight of the label claim and contains notmore than about 1% by weight of total impurities, at the end of thegiven storage period.
 42. The posaconazole liquid composition as claimedin claim 1, wherein the pH of the composition ranges from about pH 2 toabout pH 4.